Looks Like CJD But Isn't Always

by John Gever John Gever Deputy Managing Editor, MedPage Today
November 19, 2013

Action Points

Patients suspected to have CJD should be tested for other rare but treatable conditions.

Note that the findings suggest that cerebrospinal fluid neuronal surface antigens analysis should be included in the diagnostic workup of patients with rapidly progressive central nervous system syndromes.

Patients suspected to have Creutzfeldt-Jakob disease (CJD) should be tested for other rare but treatable conditions, said researchers with case reports to back up the recommendation.

Testing in 346 patients thought possibly to have CJD because of rapid neurological deterioration showed that six had antibodies to neuronal surface antigens in cerebrospinal fluid (CSF) indicative of other diseases, with five showing improvement and one stabilized after treatment based on the new diagnoses, according to Francesc Graus, MD, PhD, of the Hospital Clinic in Barcelona, and colleagues.

In a separate report, two researchers at Yale University described a patient initially diagnosed with CJD who actually had an autoimmune encephalitis targeting voltage-gated potassium channel complexes, discovered after close analysis of the man's clinical symptoms and brain MRI scans.

Sporadic CJD occurs when normal prion proteins spontaneously refold into an abnormal configuration, which has the unique ability to catalyze other normal prions to refold into the rogue form. Over time, brain atrophy in the form of sponge-like holes sets in. There is no treatment other than supportive therapy and it is always fatal.

The condition is usually first detected because of clinical symptoms, notably a rapidly progressing dementia and motor disability. In addition, noted Graus and colleagues in their report, "the diagnosis is supported by the presence of characteristic electroencephalographic (EEG) and MRI findings as well as increased levels of neuronal injury markers in the CSF, particularly the 14-3-3 protein."

But 14-3-3 protein testing can yield false-negative and false-positive findings, so it is not definitive, the researchers indicated. MRI and EEG testing are not perfect either. Consequently, some patients with suspected CJD may actually have other rare conditions

For the current study, Graus and colleagues -- who run a reference lab for 14-3-3 protein testing -- analyzed all 346 patient CSF samples sent to them in 2012 for the presence of anti-neuronal surface antigen antibodies as well as for 14-3-3 protein. The analysis also included CSF samples from 49 patients with pathologically confirmed CJD in a registry.

Of the 346 samples, 10 contained antibodies that bound to rat brain sections, indicating that they targeted some protein in the brain. Five of the targets were positively identified in cell-based assays: CASPR2, LGI1, NMDAR, AQP4, and Tr/DNER (delta/notch-like epidermal growth factor–related receptor). Another target was localized to hippocampal neurons but was not specifically identified. Graus and colleagues gave up on the other four after failing to detect binding in cultures of dissociated rat hippocampal neurons.

No evidence of anti-neuronal surface antigen antibodies was seen in the 49 patients with definite CJD.

The positive antibody results in the six patients led to new diagnoses and treatments in each case. The patient with anti-NMDA receptor antibodies was treated with electroconvulsive therapy (prior to the antibody detection), venlafaxine (Effexor), and quetiapine (Seroquel) and showed improvement.

Patients with the antibodies against CASPR2, LGI1, AQP4, and Tr/DNER received corticosteroids, with other immunomodulatory treatments in two cases. Three of the patients improved; the one with anti-Tr/DNER antibodies showed no further deterioration.

Finally, the patient with the unidentified hippocampal antibody target was diagnosed with small-cell lung cancer and was treated accordingly, with resolution of neurological symptoms. They returned several months later, however, when the cancer recurred.

Graus and colleagues concluded that "a low, but clinically relevant, number of patients with suspected CJD have neuronal surface antigen antibody-associated neurological disorders that are potentially responsive to immunotherapy."

They also noted that five of the six patients with positive antibody results were negative for 14-3-3 protein, but the patient with anti-LGI1 antibodies also tested positive for 14-3-3 -- meaning that the presence of the latter does not exclude an autoimmune diagnosis.

Yoo and Hirsch reported on a 58-year-old man who had received a diagnosis of CJD at a different institution, following several weeks of intermittent confusion and facial twitching. After the CJD diagnosis, he suffered a new-onset generalized seizure while sleeping, which brought him to Yale.

The workup there cast doubt on the CJD diagnosis, revealing the presence of faciobrachial dystonic seizures, which are inconsistent with CJD but very consistent with autoimmune targeting of potassium channels. Serum testing revealed antibodies against LGI1, a voltage-gated potassium channel. Yoo, Hirsch, and other members of the treatment team determined that this autoimmune syndrome was responsible for the man's symptoms and initiated treatment with steroids and phenytoin.

The seizures disappeared quickly and, over the next several months, the anti-LGI1 antibodies vanished as well and the man's cognition returned to normal. No recurrence of symptoms was seen for more than a year after the autoimmune diagnosis was made, Yoo and Hirsch reported.

Notably, this man also tested positive for 14-3-3 protein in CSF. But, the researchers said, he lacked "definite restricted diffusion" on MRI scans, which "should have raised a red flag against the diagnosis of CJD." Also, doctors making the initial diagnosis apparently mistook the patient's faciobrachial dystonic seizures for myoclonus.

Yoo and Hirsch wrote that the anti-potassium channel autoimmune syndrome "is the most common treatable condition that mimics CJD," and therefore should be ruled out in all patients suspected of having CJD.

The study by Graus and colleagues was funded by the NIH and the Fundació la Marató TV3. The report by Yoo and Hirsch had no external funding.

One of Graus's co-authors reporting receiving royalties on patents covering autoantibody tests and has received research funding from Euroimmun.

All other authors of both studies declared they had no relevant financial interests.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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